Project 3: Memory decline is the earliest manifestation of Alzheimer's disease (AD), and can be detected up to 10 years before the diagnosis is fully established by current methods. Numerous investigations indicate that decline in memory performance with advancing age is common and may occur in the absence of AD. It remains uncertain whether this failure in memory performance reflects a prodromal stage of AD or is a normal variation of aging. Early AD targets the hippocampal formation, a structure comprised of distinct anatomical regions. We have recently developed a functional MR protocol that can detect differential activation of these separate hippocampal, and in a series of pilot studies have found that AD patients have dysfunction in all regions compared to age-matched controls. When we employed this fMRI protocol to study elderly individuals with memory decline, but without dementia, two patterns of hippocampal activation emerged: One pattern had predominant dysfunction in the entorhinal region and was indistinguishable to the pattern seen in AD; and a second pattern had dysfunction restricted to single hippocampal region, the subiculum. The primary goal of this proposal is to determine whether this fMRI protocol can detect a regional pattern of hippocampal dysfunction that is associated with AD, and whether it can reliably dissociate healthy elderly with memory decline into those with and or without prodromal AD. 20 patients with probable AD, 40 elderly with normal with normal memory, and 80 elderly with memory decline will be evaluated at baseline. Elderly with and without memory decline will be followed prospectively and some are predicted to progress to AD at follow-up. Analysis will determine whether elderly with an AD-like hippocampal activation pattern at baseline have different clinical courses and a different incidence of AD. The fMRI protocol will also be employed to identify topographical networks within the hippocampus associated with normal memory processing.